Sip1 – novel mechanism regulating pain perception

Harmful events that can result in tissue injury are noxious for an organism. To evade such events the perception of pain is an extremely important function of the body. The transduction of noxious stimuli is warranted through specialized ion channels and receptors expressed by primary nociceptive neurons. The molecular mechanisms regulating the relevant genes and ion channels for pain processing are only poorly understood so far.

The Smad-interacting protein 1 (Sip1/ Zfhx1b/Zeb2) is a 2-handed zinc finger DNA-binding protein with essential functions in the embryonic development of the neocortex, the neural crest, and the cardiovascular system. In most assays, it functions as a transcriptional repressor whose activity is modulated by association with co-repressors, but Sip1 can function as an activator of transcription as well. Homozygous deletion of this gene in mice is embryonically lethal, whereas heterozygous knockout mice are viable and display no obvious malformations apart from defects of the corpus callosum. Mutant mice lacking one Zfhx1b allele were analyzed in the German Mouse Clinic. The primary and secondary nociception-screen, which is led by Prof. Zimmer and Ildikó Rácz from the University of Bonn, revealed that heterozygous mutants show decreased thermal pain responses whereas the mechanical pain perception remained unaffected.

Based on these results the Bonn scientists together with Monica Jeub and Heinz Beck investigated if morphological or functional alterations are responsible for the observed phenotype. Electrophysiological results and modelling experiments showed that repetitive firing of capsaicin/heat-sensitive nociceptive DRG neurons was markedly impaired. The analysis of the voltage-gated currents underlying repetitive firing revealed that sodium and potassium currents are changed. Taking together the data from the electrophysiological and the modelling experiments, the alterations point towards a depolarization-induced block of action potential propagation at the primary nociceptive neuron t-junction. The scientists conclude that Sip1 controls the transduction properties of heat-sensitive primary sensory neurons and thus thermal pain sensitivity in a novel manner via coordinated changes in primary nociceptive neuron voltage-gated ion channels.